Behavioral effects and binding affinities of the fentanyl derivative OHM3507.
Several fentanyl derivatives have been reported to have novel pharmacologies that might be exploited for developing alternate approaches to the treatment of pain. The purpose of the current series of studies was to evaluate OHM3507, a novel fentanyl derivative reported to have an unusual pharmacological profile in nonprimate species. Similar to several other fentanyl derivatives with clinical potential, OHM3507 had the highest affinity (IC50 = 10 nM) for mu ([3H]D-Ala2,N-Me-Phe4,Gly5-OH-labeled) receptors with 6- and 176-fold lower affinity for delta ([3H]D-Pen2-D-Pen5-labeled), and kappa ([3H]ethylketocyclazocine-labeled) receptors, respectively. In rhesus monkeys, OHM3507 shared discriminative stimulus effects with morphine, increased tail-withdrawal latencies in a warm-water procedure of antinociception, decreased ventilation in monkeys breathing normal air or 5% CO2, and failed to modify accuracy on acquisition and performance tasks up to doses that decreased rates of food-maintained responding. The opioid antagonists naltrexone and naltrindole antagonized the behavioral effects of OHM3507 in a manner that was consistent with mu-receptor mediation. Although OHM3507 appeared to have low efficacy opioid actions in nonprimate species, results from the current studies clearly show this compound to have strong, fentanyl-like mu agonist actions in rhesus monkeys. These results provide another example of the sometimes poor predictability in the behavioral pharmacology of fentanyl derivatives among species, in this case between monkeys and rats, mice and rabbits, and demonstrates the need for evaluating new drugs under a broad range of conditions to increase the probability of identifying novel compounds that can be used to treat pain.
France
C P
CP
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans 70119, USA.
Ahn
S C
SC
Brockunier
L L
LL
Bagley
J R
JR
Brandt
M R
MR
Winsauer
P J
PJ
Moerschbaecher
J M
JM
D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006168:Guinea Pigs; D008253:Macaca mulatta; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects
D000701:Analgesics, Opioid; C111107:OHM 3507; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D005283:Fentanyl